[unreadable] Formation of specialized domains within cell membranes is currently an area of intense experimental work because evidence for transient formation of such domains, referred to in some contexts as lipid rafts, is strongly implicated in cell signaling and interactions with the cytoskeleton. Most of these studies are largely empirical experimental projects whose design is limited by the lack of a model that explains why such domains form or predicts which biochemical or mechanical perturbations will affect them. Two recent collaborations between the PI of the parent grant and each of the two Latvian collaborators suggest that physical-chemical models may account for domain formation by the phosphoinositide systems studied in the parent project, and this application seeks to expand this work to test different hypotheses for the biochemical interactions that stabilize or remodel membrane lipid domains. [unreadable] The parent grant for this project focuses on the role of phosphoinositides and their effects on actin binding proteins including gelsolin. A key aspect of the project is to define the structures that these highly anionic lipids form in mixed lipid bilayers designed to mimic the cell membrane and to determine how different arrangements of lipids within the plane of the bilayer affects interactions with proteins. The work of the foreign collaborators will focus on two theoretical approaches to provide explanation for the experimental results and prediction for future experiments. In one approach, continuum theories developed by Prof. Cebers will study the steric and electrostatic effects that control domain formation in membranes by analogy with phase transitions in magnetic systems. In the second approach molecular dynamics simulations headed by Dr. Liepina will model the formation of phosphoinositide clusters in bilayer models with and without addition of peptide ligands that have been shown experimentally to facilitate the formation of lipid domains. [unreadable] The overall goal of this project is to provide a theoretical basis by which to understand how phosphoinositides distribute in the mixed lipid/peptide environment of the cell membrane and to evaluate how changes in such distributions may impact cell signaling [unreadable] This research will be done primarily in Latvia at the University of Latvia in collaboration with Andrejs Cebers and at the Latvian Institute in collaboration with Inta Liepina. [unreadable]